Comparison of ion transport determinants between a TMEM16 chloride channel and phospholipid scramblase.
Two TMEM16 family members, TMEM16A and TMEM16F, have different ion transport properties. Upon activation by intracellular Ca2+, TMEM16A-a Ca2+-activated Cl- channel-is more selective for anions than cations, whereas TMEM16F-a phospholipid scramblase-appears to transport both cations and anions. Under saturating Ca2+ conditions, the current-voltage (I-V) relationships of these two proteins also differ; the I-V curve of TMEM16A is linear, while that of TMEM16F is outwardly rectifying. We previously found that mutating a positively charged lysine residue (K584) in the ion transport pathway to glutamine converted the linear I-V curve of TMEM16A to an outwardly rectifying curve. Interestingly, the corresponding residue in the outwardly rectifying TMEM16F is also a glutamine (Q559). Here, we examine the ion transport functions of TMEM16 molecules and compare the roles of K584 of TMEM16A and Q559 of TMEM16F in controlling the rectification of their respective I-V curves. We find that rectification of TMEM16A is regulated electrostatically by the side-chain charge on the residue at position 584, whereas the charge on residue 559 in TMEM16F has little effect. Unexpectedly, mutation of Q559 to aromatic amino acid residues significantly alters outward rectification in TMEM16F. These same mutants show reduced Ca2+-induced current rundown (or desensitization) compared with wild-type TMEM16F. A mutant that removes the rundown of TMEM16F could facilitate the study of ion transport mechanisms in this phospholipid scramblase in the same way that a CLC-0 mutant in which inactivation (or closure of the slow gate) is suppressed was used in our previous studies.


Effects of the deleted form of hepatocyte growth factor on serum hyaluronate levels in rats with liver cirrhosis.
Effects of the deleted form of hepatocyte growth factor (dHGF) on serum hyaluronate levels, an index for liver cirrhosis, were studied in rats. The levels of serum hyaluronate increased in rats with dimethylnitrosamine- or carbontetrachloride-induced cirrhotic liver with prolongation of prothrombin time, which indicates disorder of liver function. Daily intravenous injection of dHGF reduced the elevated serum hyaluronate levels with improvement of the prolonged prothrombin time. These results suggest that the amelioration of hepatic function disorder by dHGF leads to a reduction of the increased serum hyaluronate levels.


Impact of COVID-19 on medical treatment patterns in gynecologic oncology: a MITO group survey.
COVID-19 is a global public health emergency. The increasing spread of COVID-19 presents challenges for the clinical care of patients with gynecological tumors. The Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) performed a survey to evaluate the impact of the COVID-19 pandemic on medical treatment of gynecological cancer, with a focus on chemotherapy and oral treatment with poly(ADP)-ribose polymerase inhibitors (PARP-i). The survey consisted of a self-administered online questionnaire, sent via email between November 2020 and January 2021 to all members of MITO group. Forty-nine centers completed the questionnaire. The majority of respondents (83%) use screening tests to determine COVID-19 status in patients who were to undergo chemotherapy or oral medications. All respondents to our survey continued cancer therapy in patients who tested negative for COVID-19 during the pandemic. Seventy-three percent of respondents declared they stopped treatment with chemotherapy or PARP-i only after a positive swab and resumed therapy when negative tests were confirmed. COVID-19 positivity impacted patterns of treatment in patients diagnosed with ovarian cancer within the MITO group. Further investigations are needed to evaluate whether these modifications influence oncological clinical outcomes.


Structural basis of VDR-DNA interactions on direct repeat response elements.
The vitamin D receptor (VDR) forms homo- or heterodimers on response elements composed of two hexameric half-sites separated by 3 bp of spacer DNA. We describe here the crystal structures at 2.7-2.8 A resolution of the VDR DNA-binding region (DBD) in complex with response elements from three different promoters: osteopontin (SPP), canonical DR3 and osteocalcin (OC). These structures reveal the chemical basis for the increased affinity of VDR for the SPP response element, and for the poor stability of the VDR-OC complex, relative to the canonical DR3 response element. The homodimeric protein-protein interface is stabilized by van der Waals interactions and is predominantly non-polar. An extensive alpha-helix at the C-terminal end of the VDR DBD resembles that found in the thyroid hormone receptor (TR), and suggests a mechanism by which VDR and TR discriminate among response elements. Selective structure-based mutations in the asymmetric homodimeric interface result in a VDR DBD protein that is defective in homodimerization but now forms heterodimers with the 9-cis retinoic acid receptor (RXR) DBD.


Acute appendicitis: influence of early pain relief on the accuracy of clinical and US findings in the decision to operate--a randomized trial.
To determine the influence of early pain relief on the diagnostic performance of ultrasonography (US) and on the appropriateness of the surgical decision. A prospective randomized, double-blind placebo-controlled trial with morphine was conducted. A visual analog scale was used to evaluate pain in 340 patients aged 16 years or older. US was performed with a standardized protocol. Diagnosis was confirmed at histologic analysis or, in the patients released without surgery, at follow-up. One hundred seventy-five patients were injected with morphine, and 165 were injected with the placebo. Pain relief was stronger in the morphine group. In the morphine group, US had lower (71.1%) sensitivity (difference, -9.5%; 95% CI, -18.5%, -0.5%) and higher (65.2%) specificity (difference, 11.4%; 95% CI, 1.0%, 21.8%). This group had also a higher positive predictive value (64.6%) and a lower negative predictive value (71.4%), but the differences between this group and the placebo group were not statistically significant. Among female patients, the decision to operate was appropriate more often in the morphine group (75.8%), but the difference between this group and the placebo group was not statistically significant (5.1%; 95% CI, -7.4%, 17.6%). In male patients and overall, opiate analgesia did not influence the appropriateness of the decision. The appropriateness to discharge patients without surgery was 100% in all groups. Morphine does not improve US-based diagnosis of appendicitis.


Dosimetric Limitations in Treating Breast Cancer with Accelerated Partial Breast Irradiation Using Strut Adjusted Volume Implant (SAVI).
We present one case of accelerated partial breast irradiation (APBI) using strut adjusted volume implant (SAVI) where there were limitations in delivering the dose as per the standard guidelines. The device was placed close to both the chest wall and the skin with little tissue surrounding the tip. Two plans were made in an attempt to achieve the standard therapeutic doses without over-treating the chest wall or the skin. Similar cases reported in the literature were reviewed. The dosimetry of the two plans was compared to the cases discussed in the literature.


Case report: a very large dissection in the left anterior descending coronary artery of a 56-year-old man.
Spontaneous coronary artery dissection (SCAD) is a rare condition that usually occurs in relatively young patients who are predominantly female. Seldom it could be a cause of acute myocardial ischemia leading to a sudden cardiac death. SCAD consists of intramural hematoma formation or, rarely, intimal tears that initiate and propagate the dissection in the vessel wall. In rare cases, the SCAD occurs in male patients. We report the case of a 56-year-old man with acute myocardial infarction who was successfully treated via systemic thrombolysis in a peripheral hospital. Associated conditions were thrombosis of right femoral artery in the past and high platelet count (800,000/mm3). After 1 month, elective coronary angiography revealed a very diffuse spiral dissection of the left anterior descending artery; hence, our choice of medical treatment consisted of double oral antiplatelet therapy (clopidogrel 75 mg plus aspirin 325 mg once daily). After a 2-year follow-up, there was absence of both angina and myocardial ischemia and there was a decrease in platelet count. Many strategies could be considered in patients with SCAD, such as PCI, bypass surgery, or conservative medical management. In general, the long-term prognosis of patients with SCAD is considered favorable if they survive the acute phase.


A maximum common substructure-based algorithm for searching and predicting drug-like compounds.
The prediction of biologically active compounds is of great importance for high-throughput screening (HTS) approaches in drug discovery and chemical genomics. Many computational methods in this area focus on measuring the structural similarities between chemical structures. However, traditional similarity measures are often too rigid or consider only global similarities between structures. The maximum common substructure (MCS) approach provides a more promising and flexible alternative for predicting bioactive compounds. In this article, a new backtracking algorithm for MCS is proposed and compared to global similarity measurements. Our algorithm provides high flexibility in the matching process, and it is very efficient in identifying local structural similarities. To predict and cluster biologically active compounds more efficiently, the concept of basis compounds is proposed that enables researchers to easily combine the MCS-based and traditional similarity measures with modern machine learning techniques. Support vector machines (SVMs) are used to test how the MCS-based similarity measure and the basis compound vectorization method perform on two empirically tested datasets. The test results show that MCS complements the well-known atom pair descriptor-based similarity measure. By combining these two measures, our SVM-based model predicts the biological activities of chemical compounds with higher specificity and sensitivity. Supplementary data are available at Bioinformatics online.


Glutaminase 1 expression in colorectal cancer cells is induced by hypoxia and required for tumor growth, invasion, and metastatic colonization.
Cancer cells re-program their metabolic machinery to meet the requirements of malignant transformation and progression. Glutaminase 1 (GLS1) was traditionally known as a mitochondrial enzyme that hydrolyzes glutamine into glutamate and fuels rapid proliferation of cancer cells. However, emerging evidence has now revealed that GLS1 might be a novel oncogene involved in tumorigenesis and progression of human cancers. In this study, we sought to determine whether GLS1 implicated in invasion and metastasis of colorectal carcinoma, and its underlying molecular mechanism. By analyzing a large set of clinical data from online datasets, we found that GLS1 is overexpressed in cancers compared with adjacent normal tissues, and associated with increased patient mortality. Immunohistochemical analysis of GLS1 staining showed that high GLS1 expression is significantly correlated with lymph node metastasis and advanced clinical stage in colorectal cancer patients. To investigate the underlying mechanism, we analyzed the Cancer Genome Atlas database and found that GLS1 mRNA expression is associated with a hypoxia signature, which is correlated with an increased risk of metastasis and mortality. Furthermore, reduced oxygen availability increases GLS1 mRNA and protein expression, due to transcriptional activation by hypoxia-inducible factor 1. GLS1 expression in colorectal cancer cells is required for hypoxia-induced migration and invasion in vitro and for tumor growth and metastatic colonization in vivo.


Role of tissue eosinophils in chronic rhinosinusitis-associated olfactory loss.
Olfactory dysfunction is 1 of the hallmark symptoms of chronic rhinosinusitis (CRS). Eosinophilic inflammation has been implicated as a potential causative factor. However, prior studies have been limited by retrospective study designs, concomitant use of systemic corticosteroids, and other confounding factors. CRS and healthy non-CRS control subjects undergoing endoscopic sinus or skull-base surgery were prospectively enrolled and completed olfactory testing utilizing the 40-item Smell Identification Test (SIT) immediately prior to surgery. Histopathological evaluation of tissue excised from the ethmoid bulla was performed by a pathologist in a blinded fashion. Disease severity and patient-reported outcomes were measured via the Lund-Mackay computed tomography (CT) grading system and 22-item Sino-Nasal Outcome Test (SNOT-22), respectively. The associations between olfactory function, tissue eosinophilia, and disease severity were analyzed using Spearman rank order correlation and multiple linear regression. Twenty-seven (27) subjects with CRS without nasal polyps (CRSsNP), 32 subjects with CRS with nasal polyps (CRSwNP), and 10 healthy non-CRS controls were enrolled. CRSwNP was associated with higher mean tissue eosinophil counts (71.6 vs 28.1 eosinophils/high-power field [HPF], p < 0.05) and lower age/sex-adjusted SIT scores (-17.4 vs -6.2, p < 0.001) when compared to CRSsNP. SIT scores were strongly negatively correlated with tissue eosinophil counts in CRSwNP (r = -0.60, p = 0.0003), but not CRSsNP (r = 0.16, p = 0.42). The correlation between olfactory function and tissue eosinophilia in CRSwNP persisted after adjusting for disease severity. Tissue eosinophilia is associated with olfactory loss in CRSwNP, independent of disease severity. These results suggest a possible role for eosinophils or eosinophil-associated cytokines in CRS-associated olfactory loss.


Mobile linkers on DNA-coated colloids: valency without patches.
Colloids coated with single-stranded DNA (ssDNA) can bind selectively to other colloids coated with complementary ssDNA. The fact that DNA-coated colloids (DNACCs) can bind to specific partners opens the prospect of making colloidal "molecules." However, in order to design DNACC-based molecules, we must be able to control the valency of the colloids, i.e., the number of partners to which a given DNACC can bind. One obvious, but not very simple approach is to decorate the colloidal surface with patches of single-stranded DNA that selectively bind those on other colloids. Here we propose a design principle that exploits many-body effects to control the valency of otherwise isotropic colloids. Using a combination of theory and simulation, we show that we can tune the valency of colloids coated with mobile ssDNA, simply by tuning the nonspecific repulsion between the particles. Our simulations show that the resulting effective interactions lead to low-valency colloids self-assembling in peculiar open structures, very different from those observed in DNACCs with immobile DNA linkers.


Flare Associated with LHRH-Agonist Therapy.
The most common form of hormonal treatment for prostate cancer is luteinizing hormone-releasing hormone (LHRH)-agonist therapy. During the first 1 to 3 weeks of LHRH-agonist therapy, an initial increase in testosterone is associated with a condition known as "flare." Blockade of flare can be accomplished with a number of agents, including flutamide, bicalutamide, nilutamide, diethylstilbestrol, ketoconazole, and cyproterone acetate. Evidence from the early use of LHRHagonists suggested that flare could be serious in nature, with an exacerbation of pain, increase in uremia, development of neurologic sequelae, and possibly death. These events have been uncommonly reported of late, most probably owing to the use of flare blockade in most patients with advanced disease, as well as the fact that many patients are currently being treated with much earlier disease. Evidence is conflicting as to whether flare makes a difference in less advanced disease. A few reports have noted complications during flare in patients in whom a blockade of flare was not required, including two deaths from one institution. Reported series, however, seem to suggest that with flare blockade, acute complications are extremely uncommon. Evidence suggests that 1) advanced disease should be blocked; 2) blockade should probably include an antiandrogen beginning about 1 week prior to administration of the LHRH-agonist; and 3) that patients without advanced disease but with very high PSA levels should be considered for flare blockade.


Population effect of influenza vaccination under co-circulation of non-vaccine variants and the case for a bivalent A/H3N2 vaccine component.
Some past epidemics of different influenza subtypes (particularly A/H3N2) in the US saw co-circulation of vaccine-type and variant strains. There is evidence that natural infection with one influenza subtype offers short-term protection against infection with another influenza subtype (henceforth, cross-immunity). This suggests that such cross-immunity for strains within a subtype is expected to be strong. Therefore, while vaccination effective against one strain may reduce transmission of that strain, this may also lead to a reduction of the vaccine-type strain's ability to suppress spread of a variant strain. It remains unclear what the joint effect of vaccination and cross-immunity is for co-circulating influenza strains within a subtype, and what is the potential benefit of a bivalent vaccine that protects against both strains. We simulated co-circulation of vaccine-type and variant strains under a variety of scenarios. In each scenario, we considered the case when the vaccine efficacy against the variant strain is lower than the efficacy against the vaccine-type strain (monovalent vaccine), as well the case when vaccine is equally efficacious against both strains (bivalent vaccine). Administration of a bivalent vaccine results in a significant reduction in the overall incidence of infection compared to administration of a monovalent vaccine, even with lower coverage by the bivalent vaccine. Additionally, we found that with greater cross-immunity, increasing coverage levels for the monovalent vaccine becomes less beneficial, while introducing the bivalent vaccine becomes more beneficial. Our work exhibits the limitations of influenza vaccines that have low efficacy against non-vaccine strains, and demonstrates the benefits of vaccines that offer good protection against multiple influenza strains. The results elucidate the need for guarding against the potential co-circulation of non-vaccine strains for an influenza subtype, at least during select seasons, possibly through inclusion of multiple strains within a subtype (particularly A/H3N2) in a vaccine.


Unravelling protein -organic solvent interaction of organic solvent tolerant elastase from Pseudomonas aeruginosa strain K crystal structure.
The utilization of organic solvents as reaction media for enzymatic reactions provides numerous industrially attractive advantages. However, an adaptation of enzyme towards organic solvent is unpredictable and not fully understood because of limited information on the organic solvent tolerant enzymes. To understand how the enzyme can adapt to the organic solvent environment, structural and computational approaches were employed. A recombinant elastase from Pseudomonas aeruginosa strain K was an organic solvent tolerant zinc metalloprotease was successfully crystallized and diffracted up to 1.39 Å. Crystal structure of elastase from strain K showed the typical, canonical alpha-beta hydrolase fold consisting of 10-helices (118 residues), 10- β-strands (38 residues) and 142 residues were formed other secondary structure such as loop and coil to whole structure. The elastase from Pseusomonas aeruginosa strain K possess His-140, His-144 and Glu-164 served as a ligand for zinc ion. The conserved catalytic triad was composed of Glu-141, Tyr-155 and His-223. Three-dimensional structure features such as calcium-binding and presence of disulphide-bridge contribute to the stabilizing the elastase structure. Molecular dynamic (MD) simulation of elastase revealed that, amino acid residues located at the surface area and disulphide bridge in Cys-30 to Cys-58 were responsible for enzyme stability in organic solvents.


Weighted gene coexpression network analysis reveals negative regulation of hypertrophic cardiomyopathy by carboxylesterase 1 and cathepsin C.
Hypertrophic cardiomyopathy (HCM) is a primary cardiomyopathy characterized by hypertrophic cardiomyocytes. It is one of the leading causes of sudden death in adolescents. However, the molecular mechanism of HCM is not clear. In our study, ribonucleic acid (RNA) sequence data of myocardial tissue in HCM patients were extracted from the Gene Expression Omnibus (GEO) database (GSE130036) and analyzed by weighted gene coexpression network analysis (WGCNA). A total of 31 coexpression modules were identified. The coexpression black module significantly correlated with maximum left ventricular wall thickness (Maxi LVWT). We screened the differentially expressed mRNAs between normal tissues and HCM tissues using the dplyr and tidyr packages in R3.6.2. The genes in the black module and differentially expressed genes were further intersected. We found that the expression of carboxylesterase 1 (CES1) and cathepsin C (CTSC) was downregulated in HCM tissues and negatively correlated with Maxi LVWT. We further verified the expression of CES1 and CTSC was downregulated in HCM clinical blood and negatively correlated with Maxi LVWT. Finally, we demonstrated that overexpression of CTSC and CES1 could alleviate HCM in an HCM cell model. In summary, the study suggests that CES1 and CTSC negatively regulate the development of HCM and have potential as therapeutic and diagnostic targets for HCM.


Lumbar hernia - case report.
The author presents a case report of a rare lumbar hernia. A 69 years old woman came to our outpatient room with a big mass in the right lumbar area. The CT scan revealed a big lumbar hernia containing the right kidney, the colon and small intestine. The patient underwent an uneventful open hernioplasty with the use of a prolene mesh. Lumbar hernia occurs very rarely. Open hernioplasty with the use of a mesh is the method of choice in big hernias. Small hernias can be repaired laparoscopically.


Discovery of 1-[2-[(1S)-(3-dimethylaminopropionyl)amino-2-methylpropyl]-4-methylphenyl]-4-[(2R)-methyl-3-(4-chlorophenyl)-propionyl]piperazine as an orally active antagonist of the melanocortin-4 receptor for the potential treatment of cachexia.
A potent and selective antagonist of the melanocortin-4 receptor, 1-[2-[(1S)-(3-dimethylaminopropionyl)amino-2-methylpropyl]-6-methylphenyl]-4-[(2R)-methyl-3-(4-chlorophenyl)propionyl]piperazine (10d), was identified from a series piperazinebenzylamine attached with a N,N-dimethyl-beta-alanine side chain. This compound possessed high water solubility and exhibited good metabolic profiles. In animals, 10d showed moderate to good oral bioavailability and promoted food intake in tumor-bearing mice after oral administration.


Spectral domain optical coherence tomographic findings of bietti crystalline dystrophy.
We analyzed the OCT features of 24 eyes of 12 patients with Bietti crystalline dystrophy (BCD) with the Heidelberg HRA2-OCT. Seventeen of 24 eyes were in intermediate stage of the disease and seven in advanced stage of the disease at the time of latest OCT examination performed in 2014. Outer retinal tubulations and retinal hyperreflective dots were present in 20 of 24 eyes. The remaining four eyes had advanced disease with very thin retina. Appearance of bright plaque on top of RPE-Bruch membrane was present in all eyes. Choroidal hyperreflective spots were noted in 19 of 24 eyes. The remaining five eyes had advanced disease stage with very thin choroid. Mean central macular thickness was 163.08 μm ± 62.52 for all eyes (170.35 μm ± 56.46 in eyes with intermediate disease and 145.42 μm ± 77.2 in eyes with advanced disease). Mean subfoveal choroidal thickness was 95.37 μm ± 55.93 for the study eyes (116.47 ± 46.92 μm in eyes with intermediate disease and 44.14 μm ± 42.43 in eyes with advanced disease). Choroidal hyperreflective spots were noted in 21 of 24 eyes (87.5%). SD-OCT shows the disease progression in retinal and choroidal layers delicately in eyes with BCD and expands our knowledge about the ongoing disease process.


Treatment of acute infection.
Military injuries are classically thought of as being limited to penetrating trauma caused by gunshot and blast injuries. However, blunt trauma caused by motor vehicle crashes and crush injuries can produce severe open injuries in the extremities. Most military injuries involve a higher level of energy than is commonly seen in civilian injuries, and the environment can be austere. These factors contribute to the development of infections that appear shortly after musculoskeletal trauma. Thus, the orthopaedic surgeon must know how to treat anaerobic soft-tissue infection, including clostridial fasciitis, clostridial myonecrosis, and tetanus; bacterial necrotizing fasciitis; and both superficial and deep bacterial wound infections.


Melanin and Melanin-Related Polymers as Materials with Biomedical and Biotechnological Applications-Cuttlefish Ink and Mussel Foot Proteins as Inspired Biomolecules.
The huge development of bioengineering during the last years has boosted the search for new bioinspired materials, with tunable chemical, mechanical, and optoelectronic properties for the design of semiconductors, batteries, biosensors, imaging and therapy probes, adhesive hydrogels, tissue restoration, photoprotectors, etc. These new materials should complement or replace metallic or organic polymers that cause cytotoxicity and some adverse health effects. One of the most interesting biomaterials is melanin and synthetic melanin-related molecules. Melanin has a controversial molecular structure, dependent on the conditions of polymerization, and therefore tunable. It is found in animal hair and skin, although one of the common sources is cuttlefish (Sepia officinalis) ink. On the other hand, mussels synthesize adhesive proteins to anchor these marine animals to wet surfaces. Both melanin and mussel foot proteins contain a high number of catecholic residues, and their properties are related to these groups. Dopamine (DA) can easily polymerize to get polydopamine melanin (PDAM), that somehow shares properties with melanin and mussel proteins. Furthermore, PDAM can easily be conjugated with other components. This review accounts for the main aspects of melanin, as well as DA-based melanin-like materials, related to their biomedical and biotechnological applications.


Plant oestrogens; the cause of decreased fertility in cows. A case report.
During the stall feeding period 1982-1983, it was established that serious fertility disturbances, indicating oestrogenic stimulation, had occurred in a herd of cattle in an area supported by the College of Veterinary Medicine's ambulatory clinic. Whilst investigating the cause of these disturbances it was proven that the silage administered during this period was prepared almost entirely from pure red clover aftergrowth. The oestrogenic isoflavone content of the silage (liquid chromatograph examination) and the oestrogenic strength (bioassay) were considerably great. When feeding with the fodder was subsequently discontinued the disturbances ceased to occur and the cows became pregnant more easily. On the basis of the aforementioned incidences it was ascertained that plant oestrogens were almost certainly the cause of the fertility disturbances.


Comparing the Diagnostic Performance of HFA-PEFF and H2FPEF Scoring Systems in Heart Failure with Preserved Ejection Fraction Patients: Insights from the APOLLON Registry.
Heart failure with preserved ejection fraction is a complex and heterogeneous clinical syndrome, poses significant diagnostic challenges. The HFA-PEFF [Heart Failure Association of ESC diagnostic algorithm, P (Pretest Assessment), E (Echocardiographic and Natriuretic Peptide score), F1 (Functional testing in Case of Uncertainty), F2 (Final Aetiology)] and H2FPEF [Heavy (BMI>30 kg/m2), Hypertensive (use of ≥2 antihypertensive medications), atrial Fibrillation (paroxysmal or persistent), Pulmonary hypertension (Doppler Echocardiographic estimated Pulmonary Artery Systolic Pressure >35 mm Hg), Elderly (age >60 years), Filling pressure (Doppler Echocardiographic E/e' >9)] scoring systems were developed to aid in diagnosing heart failure with preserved ejection fraction. This study aimed to assess the concordance and clinical accuracy of these scoring systems in the 'A comPrehensive, ObservationaL registry of heart faiLure with mildly reduced and preserved ejection fractiON' cohort. A comPrehensive, ObservationaL registry of heart faiLure with mildly reduced and preserved ejection fractiON study was conducted as a multicenter, cross-sectional, and observational study; to evaluate a group of Heart failure with mildly reduced ejection fraction and heart failure with preserved ejection fraction patients who were seen by cardiologists in 13 participating centers across 12 cities in Türkiye. The study enrolled 819 patients with heart failure with preserved ejection fraction, with high probability heart failure with preserved ejection fraction rates of 40% and 26% for HFA-PEFF and H2FPEF scorings, respectively. The concordance between the 2 scoring systems was found to be low (Kendall's taub correlation coefficient of 0.242, P < .001). The diagnostic performance of both scoring systems was evaluated, revealing differences in their approach and ability to accurately identify heart failure with preserved ejection fraction patients. The low concordance between the HFA-PEFF and H2FPEF scoring systems underscores the ongoing challenge of accurately diagnosing and managing patients with heart failure with preserved ejection fraction. Clinicians should be aware of the strengths and limitations of each scoring system and use them in conjunction with other clinical and laboratory findings to arrive at an accurate diagnosis. Future research should focus on identifying additional diagnostic factors, developing more accurate and comprehensive diagnostic algorithms, and investigating alternative methods of diagnosis or stratification of patients based on different clinical characteristics.


Resistance of G mice to murine leukemia virus infection: apparent disparity in in vivo and in vitro resistances.
We observed a marked discordance between in vivo and in vitro sensitivities to Friend murine leukemia virus in G mice. In vivo resistance of G mice was more than 10(5)-fold relative to sensitive DDD mice, whereas in vitro resistance was only 50 to 100-fold. In vivo sensitivity to N- and NB-tropic Friend murine leukemia virus was recessive in (G X DDD)F1 mice, whereas in vitro sensitivity was dominant in the heterozygotes. The resistance of mouse fibroblasts was different from the resistance of fibroblasts of a certain NZB mouse strain.


Quality of life, anxiety and depression in Turkish breast cancer patients and in their husbands.
The aim of the present study is to investigate anxiety and depression levels and quality of life of Turkish breast cancer patients and their husbands with Beck depression, STAI scoring system, and EORTC-QLQ-C30 quality of life scale. Fifty-five patients with breast cancer undergoing chemotherapy who applied to Dokuz Eylul University Faculty of Medicine, Department of Oncology, and their husbands were included in this study. The series of forms including the questions regarding the demographic characteristics of the patient, Beck Depression Inventory (BDI), the State-Trait Anxiety Inventory (STAI), and EORTC-QLQ-C30 (version 3) were completed during face-to-face interviews by trained interviewers for determination of the psychological status and quality of life of the patients. The mean Beck depression scores of patients and their husbands were 13 +/- 9.3 (range 2-46) and 7.9 +/- 5.7 (range 0-27) (P = 0.001). The mean STAI scores of patients and their husbands were 44.9 +/- 8.7 (range 20-58) and 41.7 +/- 8.0 (range 26-59) (P = 0.09).Twenty-nine percent of the patients and 5.4% of the husbands (Beck Depression scores > or = 17 points) were determined as depressive. It was determined that the EORTC-QLQ C30 physical and social function scales of the patients were significantly lower than their husbands. The difference of global quality of life scores and other function scales (role, cognitive, emotional function scales) between patients and their husbands were not significant. It was found that depression of breast cancer patients were significantly higher than their husbands. But there was no significant difference between the EORTC-QLQ C30 global quality of life scores and STAI scores of the breast cancer patients and their husbands.


An objective and automated method for assessing surgical skill in endoscopic sinus surgery using eye-tracking and tool-motion data.
Assessment of surgical skill plays a crucial role in determining competency, monitoring educational programs, and providing trainee feedback. With the changing health care environment, it will likely play an important role in credentialing and maintenance of certification. The ideal skill assessment tool should be unbiased, objective, and accurate. We hypothesize that tool-motion data-how a surgeon moves his/her instruments-and eye-gaze data-what a surgeon looks at when he/she operates-contain sufficient information to quantitatively and objectively evaluate surgical skill. We investigate this hypothesis by developing a statistical model of surgery and testing the model experimentally in the context of endoscopic sinus surgery (ESS). A total of 378 trials were recorded from 7 expert and 13 novice surgeons while they were performing a series of 9 different ESS tasks. Data was collected using an electromagnetic tracker to record the surgeon's tool and endoscope motions. In addition, the location of surgeon's eye gaze was recorded using an infrared eye tracker camera. This data was fit to the statistical model and used to test the accuracy of skill assessment. The skill of expert surgeons was identified correctly for 94.6% of tasks. For surgeries performed by novice surgeons the proposed model properly recognizes the skill level with 88.6% accuracy. We present an objective and unbiased method for assessing the skill of endoscopic sinus surgeons. Experimental results show that the proposed method successfully identifies the skill levels of both expert and novice surgeons.


Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinib or imatinib.
Several retrospective studies have described the clinical manifestation of peripheral artery occlusive disease (PAOD) in patients receiving nilotinib. We thus prospectively screened for PAOD in patients with chronic phase chronic myeloid leukemia (CP CML) being treated with tyrosine kinase inhibitors (TKI), including imatinib and nilotinib. One hundred and fifty-nine consecutive patients were evaluated for clinical and biochemical risk factors for cardiovascular disease. Non-invasive assessment for PAOD included determination of the ankle-brachial index (ABI) and duplex ultrasonography. A second cohort consisted of patients with clinically manifest PAOD recruited from additional collaborating centers. Pathological ABI were significantly more frequent in patients on first-line nilotinib (7 of 27; 26%) and in patients on second-line nilotinib (10 of 28; 35.7%) as compared with patients on first-line imatinib (3 of 48; 6.3%). Clinically manifest PAOD was identified in five patients, all with current or previous nilotinib exposure only. Relative risk for PAOD determined by a pathological ABI in first-line nilotinib-treated patients as compared with first-line imatinib-treated patients was 10.3. PAOD is more frequently observed in patients receiving nilotinib as compared with imatinib. Owing to the severe nature of clinically manifest PAOD, longitudinal non-invasive monitoring and careful assessment of risk factors is warranted.


Influence of plankton metabolism and mixing depth on CO2 dynamics in an Amazon floodplain lake.
We investigated plankton metabolism and its influence on carbon dioxide (CO2) dynamics in a central Amazon floodplain lake (Janauacá, 3°23' S, 60°18' W) from September 2015 to May 2016, including a period with exceptional drought. We made diel measurements of CO2 emissions to the atmosphere with floating chambers and depth profiles of temperature and CO2 partial pressure (pCO2) at two sites with differing wind exposure and proximity to vegetated habitats. Dissolved oxygen (DO) concentrations were monitored continuously during day and night in clear and dark chambers with autonomous optical sensors to evaluate plankton metabolism. Overnight community respiration (CR), and gross primary production (GPP) rates were higher in clear chambers and positively correlated with chlorophyll-a (Chl-a). CO2 air-water fluxes varied over 24-h periods with changes in thermal structure and metabolism. Most net daily CO2 fluxes during low water and mid-rising water at the wind exposed site were into the lake as a result of high rates of photosynthesis. All other measurements indicated net daily release to the atmosphere. Average GPP rates (6.8gCm-2d-1) were high compared with other studies in Amazon floodplain lakes. The growth of herbaceous plants on exposed sediment during an exceptional drought led to large carbon inputs when these areas were flooded, enhancing CR, pCO2, and CO2 fluxes. During the period when the submerged herbaceous vegetation decayed phytoplankton abundance increased and photosynthetic uptake of CO2 occurred. While planktonic metabolism was often autotrophic (GPP:CR>1), CO2 out-gassing occurred during most periods investigated indicating other inputs of carbon such as sediments or soils and wetland plants.


[Epithelioid renal angiomyolipoma].
To issue the existence of a variety of angiomyolipoma, named epithelioid, with different histological and clinic properties. We report the case of a 17 year old female, with Bourneville's disease, who was discovered to have a solid renal mass suggestive of carcinoma in a control CT scan, adjacent to other smaller masses identified as angiomyolipomas. After several tumorectomies, the suspicious mass, 4 cm in size, was diagnosed as epithelioid angiomyolipoma, with immunohistochemical confirmation of capacity for HMB45, and negative vimentin and keratin. Despite the possibility of coexistence of adenocarcinoma and angiomyolipoma, the existence of an epithelioid variety cannot be discarded, mainly in patients with phakomatosis. The indications for surgery are the same than for the rest of renal masses. Nevertheless, follow-up criteria must be stricter due to the possibility of torpid outcome in terms of dissemination of this infrequent variety of angiomyolipoma.


Anatomical and physiological basis for the allometric scaling of cisplatin clearance in dogs.
Cisplatin is a platinum-containing cytotoxic drug indicated for the treatment of solid tumors in veterinary and human patients. Several of the algorithms used to standardize the doses of cytotoxic drugs utilize allometry, or the nonproportional relationships between anatomical and physiological variables, but the underlying basis for these relationships is poorly understood. The objective of this proof of concept study was to determine whether allometric equations explain the relationships between body weight, kidney weight, renal physiology, and clearance of a model, renally cleared anticancer agent in dogs. Postmortem body, kidney, and heart weights were collected from 364 dogs (127 juveniles and 237 adults, including 51 dogs ≥ 8 years of age). Renal physiological and cisplatin pharmacokinetic studies were conducted in ten intact male dogs including two juvenile and eight adult dogs (4-55 kg). Glomerular filtration rate (GFR), effective renal plasma flow, effective renal blood flow, renal cisplatin clearance, and total cisplatin clearance were allometrically related to body weight with powers of 0.75, 0.59, 0.61, 0.71, and 0.70, respectively. The similar values of these diverse mass exponents suggest a common underlying basis for the allometry of kidney size, renal physiology, and renal drug handling.


Activation of integrin-ERBB2 signaling in undifferentiated thyroid cancer.
Undifferentiated thyroid carcinoma is one of the most aggressive human cancers. Although genetic changes underlying this aggressive cancer remain to be elucidated, RAS mutations have been frequently identified in it. Mice harboring a mutant thyroid hormone receptor Thrb(PV) (Thrb(PV/PV) ) spontaneously develop differentiated follicular thyroid carcinoma similar to human thyroid cancer. We recently demonstrated that targeting a RAS mutation (Kras(G12D) ) to the thyroid of Thrb(PV/PV) mice (Thrb(PV/PV) Kras(G12D) mice) promotes initiation and progression of undifferentiated thyroid cancer. To uncover genes destined to drive the aggressive cancer phenotype, we used cDNA microarrays to compare the gene expression profiles of thyroid cells of Kras(G12D) mice and thyroid tumor lesions of Thrb(PV/PV) and Thrb(PV/PV) Kras(G12D) mice. Analyses of microarray data identified 14 upstream regulators that were significantly altered in thyroid tumors of Thrb(PV/PV) and Thrb(PV/PV) Kras(G12D) mice. Most of these genes with altered expression function as key regulators in growth factor-induced signaling. Further analysis identified gene expression profiles of markedly elevated integrin levels, acting as upstream activators to stimulate ERBB2-mediated downstream signaling in thyroid tumors of Thrb(PV/PV) Kras(G12D) mice. The present studies uncovered integrin-activated ERBB2 signaling as one of the mechanisms in synergy between TRβPV and KRASG12D signaling to promote aggressive tumor growth in undifferentiated thyroid cancer.


Electrostatic effects in hemoglobin: electrostatic energy associated with allosteric transition and effector binding.
The pH dependence of the summed electrostatic stabilization for deoxy- and liganded hemoglobin was computed for several ionic strength values. The computed contribution to the stabilization of deoxyhemoglobin by binding of 2,3-diphosphoglycerate in the beta cleft compared well with experimental binding behavior for human hemoglobin A0 and hemoglobin F. The contribution of diphosphoglycerate binding to the alkaline Bohr effect was computed correctly for both hemoglobins A0 and F. The computed effects of simultaneous binding of diphosphoglycerate and formation of Val-1 beta carbamino adducts suggested a competition between these effectors. A direct competition was formulated between these two effectors, with extension to include a simple anion such as chloride or bicarbonate binding in competition with diphosphoglycerate but not with Val-1 beta carbamino formation. This model was found to hold at pH 7.3-7.4 over a range of concentrations of the effectors involved and to predict the pH dependence of Val-1 beta carbamino formation over the pH range 7.0-8.0. The pH dependence of the computed differential stability of liganded vs. unliganded hemoglobin A compared well with observation.


Prognostic value of serum phosphate levels in sepsis: a systematic review and meta-analysis.
There remain controversies over the conclusion of different serum phosphate levels as prognostic predictors of sepsis patients. As such, this study investigated the association between different serum phosphate and the prognosis of sepsis. Data from PubMed, Embase, Cochrane Library, and Web of Science were systematically retrieved from the inception of databases to June 1, 2023 and independently screened and extracted by two authors. Binary variables in the study were estimated as relative risk ratio (RR) and 95% confidence interval (CI), and continuous variables were estimated as mean and standard deviation. The Newcastle-Ottawa Scale (NOS) was employed to evaluate the quality of the included studies, and subgroup analysis and sensitivity analysis were performed for all outcomes to explore the sources of heterogeneity. Ten studies were included in this study including 38,320 patients with sepsis or septic shock. Against normal serum phosphate levels, a high serum phosphate level was associated with an elevated all-cause mortality risk (RR = 1.46; 95% CI [1.22-1.74]; P = 0.000) and prolonged Intensive Care Unit (ICU) length of stay (LOS) (WMD = 0.63; 95% CI [0.27-0.98]; P = 0.001). However, there was no significant difference in the in-hospital LOS (WMD = 0.22; 95% CI [-0.61-1.05]; P = 0.609). A low serum phosphate level was not significantly associated with the all-cause mortality risk (RR = 0.97; 95% CI [0.86-1.09]; P = 0.588), ICU LOS (WMD = -0.23; 95% CI [-0.75-0.29]; P = 0.394) and in-hospital LOS (WMD = -0.62; 95% CI [-1.72-0.49]; P = 0.274). Sepsis patients with high serum phosphate levels before therapeutic interventions were associated with a significant increase in the all-cause mortality risk, prolonged ICU LOS, and no significant difference in in-hospital LOS. Sepsis patients with low serum phosphate levels before interventions may have a reduced risk of all-cause mortality, shorter ICU LOS, and in-hospital LOS, but the results were not statistically significant.


Influence of serum prolactin on semen characteristics and sperm function.
The role of serum prolactin (sPRL) in male infertility is still unclear. For assessing the clinical significance of prolactin determination during infertility investigation, serum samples of 204 males attending the Infertility Clinic of Heidelberg were examined during a 1-year period. None of the patients exhibited galactorrhoea or complained of impotence. Results were correlated with age, duration of infertility, sperm count, motility, morphology, viability, and other parameters of routine sperm analysis and postcoital testing (PCT). Additionally, in vitro sperm penetration testing (SCMPT) in cervical mucus of partners and donors was performed as an important measure of functional sperm capacity. The subsequent pregnancy rate was determined after 6 months. Prolactin levels ranged from 1.4 to 24.7 ng/mL, with a median of 5 ng/mL. Only one patient had prolactin levels out of the normal range (greater than 20 ng/mL). No significant correlation of sPRL concentration was found with results of semen analysis, PCT outcome, or SCMPT. The functional sperm capacity was better in the groups of patients with sPRL above the median level (P less than .005). No significant difference in pregnancy rate was found between the high (greater than 5 ng/mL) and low (less than or equal to 5 ng/mL) prolactin groups; these were 20% and 26%, respectively. The results suggest that routine screening of asymptomatic male patients during infertility investigation for sPRL concentration is not helpful for assessing fertility prognosis. Prolactin should be preferentially determined in patients with clinical symptoms of hyperprolactinemia to exclude pituitary adenoma.


Targeted system approach to ethylene biosynthesis and signaling of a heat tolerant tomato cultivar; the impact of growing season on fruit ripening.
Growing tomato in hot weather conditions is challenging for fruit production and yield. Tomato cv. Savior is a heat-tolerant cultivar which can be grown during both the Vietnamese winter (mild condition) and summer (hot condition) season. Understanding the mechanisms of ethylene biosynthesis and signaling are important for agriculture, as manipulation of these pathways can lead to improvements in crop yield, stress tolerance, and fruit ripening. The objective of this study was to investigate an overview of ethylene biosynthesis and signaling from target genes to proteins and metabolites and the impact of growing season on a heat tolerant tomato cultivar throughout fruit ripening and postharvest storage. This work also showed the feasibility of absolute protein quantification of ethylene biosynthesis enzymes. Summer fruit showed the delayed peak of ethylene production until the red ripe stage. The difference in postharvest ethylene production between winter and summer fruit appears to be regulated by the difference in accumulation of 1-aminocyclopropane-1-carboxylic acid (ACC) which depends on the putative up-regulation of SAM levels. The lack of differences in protein concentrations between winter and summer fruit indicate that heat stress did not alter the ethylene biosynthesis-related protein abundance in heat tolerant cultivar. The analysis results of enzymatic activity and proteomics showed that in both winter and summer fruit, the majority of ACO activity could be mainly contributed to the abundance of ACO5 and ACO6 isoforms, rather than ACO1. Likewise, ethylene signal transduction was largely controlled by the abundance of ethylene receptors ETR1, ETR3, ETR6, and ETR7 together with the constitute triple response regulator CTR1 for both winter and summer grown tomatoes. Altogether our results indicate that in the heat tolerant tomato cv. Savior, growing season mainly affects the ethylene biosynthesis pathway and leaves the signaling pathway relatively unaffected.


A Nano-in-Nano Polymer-Dendrimer Nanoparticle-Based Nanosystem for Controlled Multidrug Delivery.
Codelivery of multiple chemotherapeutics with different action mechanisms is a promising strategy for cancer treatment. In this study, we developed a novel polymer-dendrimer hybrid nanoparticle-based nanosystem for efficient and controlled codelivery of two model chemotherapeutics, doxorubicin (DOX) and paclitaxel (PTX). The nanosystem was characterized to have a nano-in-nano structure with a size of around 150 nm. The model drugs could feasibly be loaded into the nanosystem ratiometrically with high drug-loading contents by controlling the feeding drug ratios. Also, the model drugs could be released from the nanosystem following a sequential release manner-specifically, quick PTX release and sustained DOX release. Acidic pH was found to enhance the release of both drugs. Moreover, the nanosystem was taken up by cancer cells rapidly and efficiently, and the delivered drugs could release sustainably and efficiently in cells to reach their action targets. In vitro cytotoxicity results demonstrated that, by optimizing drug ratios, the dual-drug-loaded nanosystem could result in better antitumor efficacy than the single-drug-loaded nanosystem or free dual-drug combination. Furthermore, the dual-drug-loaded nanosystem could induce significant changes in both the nucleus and tubulin patterns synergistically. All data suggest that the nano-in-nano polymer-dendrimer hybrid nanoparticle-based nanosystem is a promising candidate to achieve controlled multidrug delivery for effective combination cancer therapy.


[Reconstruction of erythromycin macrocyclic lactone synthesis pathway in Escherichia coli].
We reconstructed the erythromycin macrocyclic lactone (6-deoxyerythronolide B, 6dEB) synthesis pathway in Escherichia coli. We first cloned all the genes needed to synthesize the 6dEB into multi-gene co-expressed vectors. Then using the recognition sequences of isoschizomers Xba I/Spe I of vectors, we assembled the related genes into a series multiple-genes recombinant plasmids pBJ144, pBJ130. The recombinant plasmids pBJ144, pBJ130 were cotransformed into BAP1 to get the recombinant BAP1(pBJ144/pBJ130). SDS-PAGE analysis showed that individual genes were expressed correctly. After inducing at low temperature, adding propionate as substrate, we validated the crude product by mass spectrometry and the 6dEB yield was about 10 mg/L. These results indicated that the synthetic pathway of 6dEB was successfully assembled and reconstructed in Escherichia coli, which will greatly facilitate the reconstruction of whole erythromycin synthesis pathway and finally help to establish a stable research platform for developing of new derivatives of erythromycin and combinatorial biosynthesis of polyketide-type antibiotics.


Effect of 3 vertical facial patterns on alveolar bone quality at selected miniscrew implant sites.
To evaluate dental alveolar bone quality among young healthy Chinese adults having 3 different vertical patterns. Three-dimensional cone-beam computed tomography images of 101 subjects (15 low-angle, 48 average-angle, and 38 high-angle) were reconstructed. Facial alveolar cortical bone thicknesses and cortical and cancellous bone densities at 4 selected miniscrew implant sites in both arches, together with cancellous bone densities of third cervical vertebrae, were measured. Bone qualities were compared among the 3 vertical pattern groups. The cortical bone thicknesses at mandibular 5-6 and 6-7 and the cortical and cancellous bone densities at maxillary and mandibular 5-6 and 6-7 were generally greater in the low-angle than in the other 2 groups. There was no similar consistent vertical pattern apparent for bone quality at the 1-1 and 1-2 sites. No significant differences in bone densities for third cervical vertebrae were found among the 3 groups. Careful selection of suitable implantation sites and sizes of the miniscrews used should be made to reduce the possible occurrence of implant loosening in patients with average-angle and high-angle vertical facial patterns in particular.


The Clinical Impact of Vagal Nerve Stimulator Implantation on Laryngopharyngeal Function in Children: A Single-Center Experience.
A vagal nerve stimulator (VNS) has been established as the treatment of choice for children with refractory epilepsy. The outcomes of the procedure have been well documented in adults but are less clear in children. The goal of our study was to review laryngopharyngeal (LP) function following VNS implantation in children. Case series with chart review. Tertiary-care children's hospital. Voice, swallowing, and sleep apnea symptoms were extracted from the charts of children who underwent VNS implantation between 2013 and 2021. A questionnaire was sent to parents of implanted children to ascertain the degree of the social and functional impact of the implant. There were 69 patients, aged 2.3 to 21.4 years old, who met the inclusion criteria. LP symptoms were most common during the first year following implantation; 26 patients (37.6%) demonstrated at least 1 symptom (voice alteration, chronic cough, sleep-disordered breathing, or dysphagia), and 15 patients required adjustments to their implant settings. The incidence of symptoms and the need to adjust VNS settings significantly dropped during years 2 to 5 and 6 to 8 (22% vs 7% and 5%, respectively, p = .0002). The mean score of the Pediatric Voice Handicap Index differed greatly from a normal control group on each subscale and the total score. LP dysfunction in children following VNS implantation is comparable to adults, with the most burden noticed during the first year after implantation. The presence of voice alterations did not correlate with the presence of dysphagia and sleep-disordered breathing. Thorough evaluation, preferably by a multidisciplinary team, is required to assess LP dysfunction postoperatively.


Cloning of trg, a gene for a sensory transducer in Escherichia coli.
Clones of trg, a gene which codes for a chemotactic transducer, were isolated linked to ColE1 and pBR322 vectors. Studies with the hybrid plasmids demonstrated unequivocally that trg is the structural gene for methyl-accepting chemotaxis protein III. The Trg protein was found to be structurally complex, electrophoresing as a series of seven bands on high-resolution sodium dodecyl sulfate-polyacrylamide gels. The multiplicity of bands is a function of the activity of cheR, which codes for a methyltransferase, and of cheB, which codes for a demethylase. It appears that Trg, a quantitatively minor transducer, resembles the two major transducer proteins, Tsr and Tar, in that all three are multiply methylated and also multiply modified in a second way which requires an active cheB gene. However, preliminary analysis of the Trg protein indicated that it is significantly less related structurally to the Tsr or Tar protein than those two transducers are to each other. This implies that the features of multiple methylation and cheB-dependent modification are likely to be critical for the common physiological functions in chemotactic excitation and adaptation performed by all three transducers.


Ruthenium-Arene-β-Carboline Complexes as Potent Inhibitors of Cyclin-Dependent Kinase 1: Synthesis, Characterization and Anticancer Mechanism Studies.
A series of Ru(II)-arene complexes (1-6) of the general formula [(η(6)-arene)Ru(L)Cl]PF6 (arene=benzene or p-cymene; L=bidentate β-carboline derivative, an indole alkaloid with potential cyclin-dependent kinases (CDKs) inhibitory activities) is reported. All the complexes were fully characterized by classical analytical methods, and three were characterized by X-ray crystallography. Hydrolytic studies show that β-carboline ligands play a vital role in their aqueous behaviour. These complexes are highly active in vitro, with the most active complex 6 displaying a 3- to 12-fold higher anticancer activity than cisplatin against several cancer cell lines. Interestingly, the complexes are able to overcome cross-resistance to cisplatin, and show much lower cytotoxicity against normal cells. Complexes 1-6 may directly target CDK1, because they can block cells in the G2M phase, down-regulate the expression of CDK1 and cyclin B1, and inhibit CDK1/cyclin B in vitro. Further mechanism studies show that the complexes can effectively induce apoptosis through mitochondrial-related pathways and intracellular reactive oxygen species (ROS) elevation.


Labor and childbirth care in maternities participating in the "Rede Cegonha/Brazil": an evaluation of the degree of implementation of the activities.
Using a judgment framework, this article analyzes the degree of implementation of the best practices in labor and childbirth care contained in the guidelines of the Rede Cegonha (RC) across Brazil. The study eligibility criteria were public and mixed hospitals located in a health region with a RC action plan in place in 2015, resulting in a total of 606 facilities distributed across the country. Three different data collection methods were used: face-to-face interviews with managers, health professionals and puerperal women; document analysis; and on-site observation. The framework was built around the five guidelines of the Labor and Childbirth component of the RC. Degree of implantation was rated as follows: adequate; partially adequate and inadequate. The performance of maternity facilities was rated as partially adequate for all guidelines except for hospital environment, which was rated as inadequate. A huge variation in degree of implementation was observed across regions, with the South and Southeast being the best-performing regions in most items. The results reinforce the need for an ongoing evaluation of the actions developed by the RC to inform policy-making and the regulation of labor and childbirth care.


Operationally invariant measure of the distance between quantum states by complementary measurements.
We propose an operational measure of distance of two quantum states, which conversely tells us their closeness. This is defined as a sum of differences in partial knowledge over a complete set of mutually complementary measurements for the two states. It is shown that the measure is operationally invariant and it is equivalent to the Hilbert-Schmidt distance. The operational measure of distance provides a remarkable interpretation of the information distance between quantum states.


In Vitro-Based Production of Virus-Tested Babaco (Vasconcellea x heilbornii, syn. Carica pentagona) in Ecuador: An Integrated Approach to an Endangered Crop.
Babaco (Vasconcellea x heilbornii), a fruit-bearing vegetatively propagated crop native to Ecuador, is appreciated for its distinctive flavor and nutritional properties. The aim of this research was to determine a functional protocol for tissue culture propagation of virus-free babaco plants including in vitro establishment, multiplication, rooting, and acclimation. First, symptomless babaco plants from a single commercial nursery were analyzed for virus detection and cared for using different disinfection treatments in the greenhouse to reduce contamination during the in vitro establishing step, and three cytokinins, 6-(γ,γ-Dimethylallylamino) purine (2IP), 6-Benzylaminopurine (BAP), and Thidiazuron (TDZ), were used to determine the best hormone for multiplication. The best treatment for plant disinfection was the weekly application of copper sulfate at the greenhouse and a laboratory disinfection using ethanol (EtOH) (70%), Clorox (2%), and a solution of povidone iodine (2.5%), with an 80% survival during in vitro plant establishment. TDZ showed a better multiplication rate when compared with other hormones, and 70% of the rooted plants were successfully acclimated at the greenhouse. Generated plants were virus-free when tested against babaco mosaic virus (BabMV) and papaya ringspot virus (PRSV), two of the most important viruses that can affect babaco. An efficient protocol to produce virus-free babaco plants was elaborated with an integrated use of viral diagnostic tools to ensure the production of healthy start material to farmers.


Evolving management of biliary tract disease.
The variety of treatments available for gallstone-related problems require a multidisciplinary approach with involvement of the surgeon, endoscopist, and radiologist. Many conditions, until recently treatable only by an open operation, can now be satisfactorily dealt with by minimally invasive or endoscopic techniques. The benefits of such techniques are immediately apparent in terms of reduced hospital stay and early patient recovery. The pace of progress, particularly in the area of laparoscopic biliary surgery, is rapid and has important implications for surgical training and resources. Careful audit and prospective trials, when appropriate, are required to determine optimum treatment strategies for patients with benign biliary disease. These are exciting times in surgery, but our enthusiasm for new techniques should not cloud time-honored surgical principles.


Biodegradability of para-aramid respirable-sized fiber-shaped particulates (RFP) in human lung cells.
Using both in vivo (inhalation) and in vitro (cell culture) studies, we previously reported that p-aramid respirable fibers (RFP--defined as respirable-sized fiber-shaped particulates) are biodegraded in lungs and lung cells of rats following exposures. The current studies were undertaken to determine whether shortening mechanisms of p-aramid RFP biodegradability are also operative in human lung cells. Cultures of human A549 lung epithelial cells (A549), primary alveolar macrophages (HBAL) (collected via bronchoalveolar lavage [BAL]) from volunteers), and co-cultures (Co) of the A549 and HBAL were incubated with p-aramid RFP for either 1 h, 1 day, or 1 week to assess RFP shortening. Lengths of RFP were measured using scanning electron microscopy (SEM) following fixation, digestion of culture tissue components, and processing. Similar to findings using rat lung cells, only slight RFP shortening was measured in A549 cultures at 1-day and 1-week post-incubation. More importantly, in HBAL and Co groups, greater transverse cleavage of p-aramid RFP was measured at 1-day and 1-week postexposure compared to 1-h HBAL or Co groups, or in any A549 groups. In contrast, cellulose RFP, a biopersistent reference control fiber, were not measurably shortened under similar circumstances. Second, p-aramid RFP were incubated either with phosphate-buffered saline (PBS), or acellular BAL fluids from human volunteers or rats and processed for SEM analysis of RFP lengths. Mean lengths of p-aramid RFP incubated with human or rat BAL fluids were substantially decreased compared to PBS. Similar to our findings with rat lung cells, components of human lung fluids coat the p-aramid RFP as a prerequisite for subsequent enzymatic cleavage by human phagocytic lung cells and this finding reinforces the concept that inhaled p-aramid RFP are likely to be biodegradable in the lungs of humans.


Methylation of adenosine in strongly alkaline medium: Preparation and Properties of o'-methyl derivatives of adenosine and N6-methyladenosine.
In strongly alkaline aqueous medium, 9-substituted adenines, including adenine nucleosides, are relatively resistant to alkylation of the ring nitrogens and the exocyclic amino group. This fact was utilized to obtain the various possible Omicron'-methyl derivatives of adenosine by dimethyl sulfate treatment of the latter in alkaline medium, followed by separation of the products on a Dowex OH-column. In strongly alkaline aqueous dimethyl sulfoxide, several derivatives additionally methylated on the amino group were obtained, including N6,O2'-dimethyladenosine, a component located recently at the 5' terminus of animal cell and viral mRNAs. The latter was also prepared by diazomethane methylation of N6-methyladenosine in the presence of SnCl2. Alkylation in alkaline medium possesses the advantage that the products are not limited to those involving etherification of cis hydroxyls and is applicable to adenine nucleosides with sugar components other than ribose. The properties of the various O'-methylderivatives, including proton magnetic resonance data, are presented in detail.


Localization of anti-clathrin antibody in the sarcomere and sensitivity of myofibril structure to chloroquine suggest a role for clathrin in myofibril assembly.
Immunofluorescence microscopy has been used to demonstrate that X22, a monoclonal antibody specific for clathrin heavy chain, localizes in repetitive bands that appear soon after the fusion of skeletal myoblasts into multinucleate fibers. This organization has been found in cultures containing myotubes that develop in vitro from explants of newborn rat hindlimb cells and in myotubes derived from the L8E63 myogenic line. Bands were also prominent in skinned fibers prepared from adult rat soleus muscle and in cardiac myocytes grown in vitro from 4-day heart ventricles. Immunofluorescence banding was localized in the sarcomere as a doublet, with one element on either side of the Z line. Evidence that supports the conclusion that the reaction with X22 antibody is specific and indicative of the localization of clathrin in the sarcomere includes: (1) Identical titration of X22 antibody reactivity with the determinant in coated vesicles and in the sarcomere. (2) Conditions (eg., pH and Tris) that disrupt clathrin baskets or prevent its assembly likewise disrupt the localization of X22 in bands. (3) Chloroquine inhibits both the normal trafficking of clathrin in the cell and X22 banding in the sarcomere. (4) Immunoblot analysis of myotube lysates reveals a single band with an electrophoretic mobility identical to the 180,000-Da clathrin heavy chain. (5) The assembly of clathrin into sarcomeric bands occurs early in the development of the myofibrillar apparatus. Quantitation of the appearance of X22 banding in primary cultures of myotubes indicates that it precedes that of other myofibrillar proteins and that assembly takes place in the following order: X22, titin, myosin heavy chain, actin, and desmin. The assembly of myosin, titin, and actin into sarcomeric bands, as well as X22, is inhibited by chloroquine. Upon prolonged exposure to chloroquine previously assembled proteins are drastically reduced or no longer evident in the sarcomere. On the basis of these results and considering the role of clathrin in intracellular transport and its capacity to interact with actin and alpha-actinin, we suggest that clathrin may have diverse roles in the assembly, integrity, and functioning of the sarcomere and its integration with the sarcolemma. The early organization of X22 into bands further suggests that clathrin may also function early in the assembly of the contractile system.


Complete Genome Sequence of Bacillus velezensis GUAL210, a Potential Biocontrol Agent Isolated from Pepper Rhizosphere.
Bacillus velezensis GUAL210 was isolated from the rhizosphere of healthy pepper plants growing in high-incidence anthracnose fields in Guizhou, China. GUAL210 could be used as a potential biocontrol agent against pepper anthracnose and other soil-borne diseases. The GUAL210 genome consisted of a single circular chromosome 4,011,788 bp in length, with an average GC content of 46.41%, and did not harbor any plasmids. A total of 4,115 protein-coding genes, 27 rRNAs, 87 tRNAs, and 12 secondary metabolite biosynthesis gene clusters were identified. The products of the gene clusters included bacilysin, surfactin, bacteriocin, bacillaene, terpene, and so on, which might help host plants inhibit pathogens. The two clusters predicted to produce terpene had not typically been found in other Bacillus spp. The findings of this study will provide valuable data to explore the biocontrol mechanisms of B. velezensis strains.


Learning curve for magnetic resonance imaging/ultrasound fusion prostate biopsy in detecting prostate cancer using cumulative sum analysis.
Targeted magnetic resonance (MR) with ultrasound (US) fusion-guided biopsy has been shown to improve detection of prostate cancer. The implementation of this approach requires integration of skills from radiologists and urologists. Objective methods for assessment of learning curves, such as cumulative sum (CUSUM) analysis, may be helpful in identifying the presence and duration of a learning curve. The aim of this study is to determine the learning curve for MR/US fusion-guided biopsy in detecting clinically significant prostate cancer using CUSUM analysis. Retrospective analysis was performed in this institutional review board-approved study. Two urologists implemented an MR/US fusion-guided prostate biopsy program between March 2015 and September 2017. The primary outcome measure was cancer detection rate (CDR) stratified by Prostate Imaging Reporting and Data System (PI-RADS) scores assigned on the MR imaging. Cumulative sum analysis quantified actual cancer detection versus a predetermined target satisfactory CDR of MR/US fusion biopsies in a sequential case-by-case basis. For this analysis, satisfactory performance was defined as >80% CDR in patients with PI-RADS 5, >50% in PI-RADS 4, and <20% in PI-RADS 1-3. Complete data were available for MR/US fusion-guided biopsies performed on 107 patients. The CUSUM learning curve analysis demonstrated intermittent underperformance until approximately 50 cases. After this inflection point, there was consistently good performance, evidence that no further learning curve was being encountered. At a new center implementing MR/US fusion-guided prostate biopsy, the learning curve was approximately 50 cases before a consistently high performance for prostate cancer detection.


Ixodes ricinus as a vector of Borrelia burgdorferi sensu lato, Anaplasma phagocytophilum and Babesia microti in urban and suburban forests.
In the suburban and urban forests in the cities of Gdansk, Sopot and Gdynia (northern Poland), Ixodes ricinus ticks should be considered as the vector of pathogenic microorganisms that may cause significant diseases in wild and domestic animals and humans. These microorganisms include etiologic agents of Lyme disease, human anaplasmosis (HA) and babesiosis: Borrelia burgdorferi sensu lato, Anaplasma phagocytophilum and Babesia microti, respectively. DNA extracts from 701 ticks collected in 15 localities were examined by PCR for the simultaneous detection of these 3 pathogens. Overall, 14 % were infected with A. phagocytophilum followed by 12.4 % with B. burgdorferi s.l. and 2.3 % with B. microti. In total, the percentage of infected females (32.9 %) was 2.4 times higher than in males (13.7 %) and 3.2 times higher than in nymphs (10.3 %). Among adult ticks (n = 303), 8.3 % were dually infected with A. phagocytophilum and B. burgdorferi s.l., 2.0 % with the agent of human anaplasmosis and B. microti and 0.3 % with borreliae and B. microti.


Diagnostic yield and safety of percutaneous native kidney biopsy in pregnancy: 20-years of single-center experience.
Percutaneous kidney biopsy is a fundamental procedure in nephrology. Although pregnancy is not a contraindication, a careful risk-benefit assessment is mandatory in pregnancy. We aimed to evaluate safety and diagnostic accuracy of percutaneous kidney biopsy in pregnancy in a single-center retrospective study. Percutaneous kidney biopsy was performed in 19 pregnant patients. Demographics, estimated glomerular filtration rates, serum albumin levels, and proteinuria levels at the time of biopsy were evaluated. Biopsy-related complications, diagnoses, and treatments during the follow-up were analyzed. In addition, delivery success, preeclampsia, early delivery, low birth weight rates, and long-term outcomes of the patients were retrieved and analyzed. Mean patient age was 27 (range 16-41) years. Median gestational week at kidney biopsy was 20th. All but one biopsies were diagnostic. Median gestational week of delivery was 35 (range 23-39) gestational weeks. Preterm delivery (< 37 gestational weeks) and low birth weight (< 2500 mg) occurred in 73.7% and 52.6% of cases, respectively. Median weight at birth was 2500 mg. The incidence of preeclampsia was 57.9%. Overall 89.5% of the children survived. Median post-biopsy follow-up was 64 months. Maternal mortality was not observed during the follow-up period. End stage kidney disease developed in one patient. The results of percutaneous kidney biopsy led to therapeutic decisions in 73.7% of cases. Although percutaneous kidney biopsy is not frequently performed during pregnancy, it is relatively safe and usually diagnostic, and may guide further follow-up.


[Progress in the genetic modification of blue flowers based on anthocyanin metabolism].
As water-soluble, natural pigments, anthocyanins are responsible for the red, purple and blue colors of many flowers, which attract pollinators to spread pollen. The colors of flowers are also essential for plants to survive in the nature and become one of the most significant characteristics of ornamental plants. In the booming floriculture industry, to produce various flower colors could increase the richness of natural colors, but it is still difficult to breed flowers with coveted blue color. The diversity of flower color is mainly determined by the types and contents of anthocyanins and their derivatives. The synthesis of delphinidin pigments is the key factor for breeding blue flowers. However, there are no structural genes in many plants to biosynthesize delphinidin pigments. Blue flowers are successfully created by genetic engineering in recent years. In this paper, using common ornamental plants as examples, we review the mechanism of plant flower coloration from the aspects of the key factors affecting the synthesis of delphinidin pigment and the production strategies of blue flowers based on the regulation of anthocyanin metabolism. Different strategies of molecular breeding could provide opportunities to improve colors of other floriculture plants and to develop anthocyanin-rich economic crops, such as colored cotton with blue fibers.


Potential role of vitexin in alleviating heat stress-induced cytotoxicity: Regulatory effect of Hsp90 on ER stress-mediated autophagy.
Cells possess multiple methods for counteracting the deleterious consequences of stress induced by physical and chemical stimuli. Heat stress causes variations in the cellular environment, leading to cellular morbidity or mortality. Natural compounds that contain phenolic antioxidants, offer various therapeutic and biological activities. Vitexin, a natural flavonoid, has been reported to treat various pathologies due to its multifaceted effects. Herein, we investigated the therapeutic efficacy of vitexin and its underlying mechanism against heat stress in human lung epithelial cells. Effect of vitexin on the expression of molecular chaperones, antioxidant enzymes, mitogen activated protein kinases (MAPKs), endoplasmic reticulum (ER)-stress and autophagy was measured by immunoblotting. qRT-PCR and EMSA were performed for Hsp90 expression and HSF-1 binding affinity. Cell viability was assessed by MTT and LDH assays. Detection of autophagy was confirmed by acridine orange staining. Role of Hsp90 inhibition on signaling pathways was elucidated by using specific chemical inhibitor, radicicol. Whereas hyperthermia reduced cell viability, result of MTT and LDH assays showed that vitexin pre-treatment enhanced cell viability after heat stress. EMSA analysis shows DNA binding affinity of HSF-1 during heat stress. Vitexin upregulated Hsp90 expression, subsequently activating ER-stress induced autophagy. Modulation of MAPKs expression and fluorescence image analysis showed vacuole accumulation, indicating autophagic flux in cells. Hsp90 inhibition reversed the effect of vitexin and activates the apoptosis pathway. Our data suggest that vitexin can protect against hyperthermic cellular injury by induction of Hsp90 expression, antioxidant activity and MAPKs via ER stress-induced autophagy.


Interleukin-4, interleukin-5, and granulocyte-macrophage colony-stimulating factor receptor expression in chronic sinusitis and response to topical steroids.
Chronic sinusitis and its associated eosinophilic infiltrate are believed to be mediated, at least in part, by the upregulation of Th-2 cytokines, including interleukin-4, interleukin-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Interleukin-4 is involved in IgE production and in eosinophil recruitment through upregulation of vascular cell adhesion molecule-1. Interleukin-5 and GM-CSF are involved in eosinophil growth and survival. The aim of this study was to investigate the expression of receptors for these cytokines in the sinus mucosa of subjects with chronic sinusitis. Using the technique of in situ hybridization to detect specific cytokine receptor messenger RNA, we studied the sinus mucosa of subjects with nonallergic chronic sinusitis, subjects with allergic chronic sinusitis, subjects with allergic chronic sinusitis treated with topical steroids, and normal controls. Our data demonstrate higher expression of interleukin-4 receptor in subjects with allergic chronic sinusitis than in controls (p < 0.001) and higher expression of interleukin-5 receptor in both subjects with nonallergic chronic sinusitis and subjects with allergic chronic sinusitis than in controls (p < 0.001, p < 0.001). The expression of interleukin-4 receptor and interleukin-5 receptor was higher in subjects with allergic chronic sinusitis than in subjects with nonallergic chronic sinusitis (p < 0.001). GM-CSF receptor expression was also found to be higher in subjects with allergic chronic sinusitis and subjects with nonallergic chronic sinusitis than in controls (p < 0.001, p < 0.001). In contrast to interleukin-4 receptor and interleukin-5 receptor, however, expression of GM-CSF receptor was higher in subjects with nonallergic chronic sinusitis than in subjects with allergic chronic sinusitis (p < 0.001). In subjects with allergic chronic sinusitis treated with topical corticosteroids, the expression of interleukin-4 receptor and interleukin-5 receptor messenger RNA levels was significantly lower than levels in patients with allergic chronic sinusitis who were not taking topical steroids (p < 0.001, p < 0.001). Steroid treatment had no effect on GM-CSF receptor messenger RNA expression. In conclusion, our data support a role for Th-2 cytokine receptors in the pathophysiology of chronic sinusitis. Further, our data lend support to the theory that differential activation of distinct cytokine pathways mediates inflammation in chronic sinusitis depending on whether there is associated allergy. Finally, treatment with topical corticosteroids has been demonstrated in chronic sinusitis to downregulate receptors for interleukin-4 and interleukin-5.


Quantitative magnetic resonance imaging analysis correlates with surgical outcome of cervical spondylotic myelopathy.
Prospective study. To investigate whether preoperative and postoperative changes of signal intensity (SI) and transverse area (TA) of the spinal cord reflect the surgical outcome in patients with cervical spondylotic myelopathy (CSM). The Second Hospital of Tangshan, Tangshan, Hebei, China. In 45 consecutive prospective patients, magnetic resonance imaging (MRI) was performed preoperatively and 3 months postoperatively. The Japanese Orthopedic Association (JOA) scale was used to quantify the neurological status at admission and of at least 12-month follow-up. Preoperative and postoperative TA of the spinal cord at the site of maximal compression and grayscale of signal intensity (GSI) were measured using the image analysis software. Ratio of transverse area (RTA) and ratio of grayscale of signal intensity (RGSI) were used to assess the extent of spinal cord re-expansion and extent of SI regression. Preoperative status and postoperative recovery were assessed in relation to MRI parameters preoperatively and postoperatively using univariate and multivariate analysis. Higher baseline JOA scores were associated with larger TA. Greater recovery rate was associated with larger preoperative and postoperative TA, along with greater RTA. Recovery rate negatively correlated with RGSI and age. Higher baseline JOA score was associated with greater recovery rate. RGSI negatively correlated with RTA. Multivariate stepwise regression analysis showed that the optimal combination of surgical outcome predictors included age, postoperative TA and RGSI. Quantitative MRI analysis in CSM may provide reliable information for the prediction of the postoperative outcome of CSM patients. MRI indicators of good outcome include the larger postoperative TA and greater RGSI.


An isotope effect on the comparative quantification of flavonoids by means of methylation-based stable isotope dilution coupled with capillary liquid chromatography/mass spectrometry.
Ionization suppression is a serious problem in liquid chromatography/mass spectrometry-based metabolomics, and stable isotope dilution-based comparative quantification is one of the most important methods of overcoming this problem. Herein, the use of [(13)C]-methylation-based stable isotope dilution for comparative quantification of flavonoids is demonstrated. This is in contrast to the equivalent deuterium labeling methylation method, which has an adverse isotope effect on reverse phase chromatography.


Host stress physiology and Trypanosoma haemoparasite infection influence innate immunity in the woylie (Bettongia penicillata).
Understanding immune function is critical to conserving wildlife in view of infectious disease threats, particularly in threatened species vulnerable to stress, immunocompromise and infection. However, few studies examine stress, immune function and infection in wildlife. We used a flow cytometry protocol developed for human infants to assess phagocytosis, a key component of innate immunity, in a critically endangered marsupial, the woylie (Bettongia penicillata). The effects of stress physiology and Trypanosoma infection on phagocytosis were investigated. Blood and faecal samples were collected from woylies in a captive facility over three months. Trypanosoma status was determined using PCR. Faecal cortisol metabolites (FCM) were quantified by enzyme-immunoassay. Mean phagocytosis measured was >90%. An interaction between sex and FCM influenced the percentage of phagocytosing leukocytes, possibly reflecting the influence of sex hormones and glucocorticoids. An interaction between Trypanosoma status and FCM influenced phagocytosis index, suggesting that stress physiology and infection status influence innate immunity.


Proton-Transfer Mechanisms at the Water-ZnO Interface: The Role of Presolvation.
The dissociation of water is an important step in many chemical processes at solid surfaces. In particular, water often spontaneously dissociates near metal oxide surfaces, resulting in a mixture of H2O, H+, and OH- at the interface. Ubiquitous proton-transfer (PT) reactions cause these species to dynamically interconvert, but the underlying mechanisms are poorly understood. Here, we develop and use a reactive high-dimensional neural-network potential based on density functional theory data to elucidate the structural and dynamical properties of the interfacial species at the liquid-water-metal-oxide interface, using the nonpolar ZnO(101̅0) surface as a prototypical case. Molecular dynamics simulations reveal that water dissociation and recombination proceed via two types of PT reactions: (i) to and from surface oxide and hydroxide anions ("surface-PT") and (ii) to and from neighboring adsorbed hydroxide ions and water molecules ("adlayer-PT"). We find that the adlayer-PT rate is significantly higher than the surface-PT rate. Water dissociation is, for both types of PT, governed by a predominant presolvation mechanism, i.e., thermal fluctuations that cause the adsorbed water molecules to occasionally accept a hydrogen bond, resulting in a decreased PT barrier and an increased dissociation rate as compared to when no hydrogen bond is present. Consequently, we are able to show that hydrogen bond fluctuations govern PT events at the water-metal-oxide interface in a way similar to that in acidic and basic aqueous bulk solutions.


Towards a theory of interrupted feelings.
The purpose of this study is to identify central aspects of feelings in relation to the experience of being a brother or sister of someone who suffers from schizophrenia. The study makes use of a hermeneutical method for the collection of data as well as for the systemizing and interpretation of data. The participants in the study were 16 siblings of persons with diagnosed schizophrenia. In total 80 interviews were done, with an average length of 50 min. A theory of interrupted feelings was developed within the tension between empirical data and preunderstanding. Mixed feelings of grief, hope, anger, guilt and shame are interrupted by four interrelated factors: ambiguous loss, the fluctuating nature of the illness, an inner prohibition of feelings and the tendency of others to invalidate the feelings. The interruption may lead to a lonely and painful experience which is difficult both to process for oneself and to share with others.


Marked genetic polymorphism of the swine steroid 21-hydroxylase gene, and its location between the SLA class I and class II regions.
Restriction fragment length polymorphism (RFLP) analysis of the swine 21-hydroxylase (CYP21) region was conducted on 31 unrelated SLA class I typed pigs, mainly Large Whites, including 15 haplotypes. Ten haplotypes were from SLA genotypic homozygotes and five were from SLA class I phenotypic homozygotes. DNA digestion with Hin dIII, TaqI and PstI, and hybridization to a 4.5-kb swine CYP21 genomic probe yielded respectively two, four and three RFLP patterns. Six patterns were identified with combined RFLP. In addition, analysis of the CYP21 region in families comprising several SLA recombinants demonstrated that the CYP21 gene lies in the DNA segment between the SLA class I and class II regions. These overall results reinforce our previous conclusion about the existence in the pig of a single 21-hydroxylase gene. The characterization of at least six CYP21 allelic patterns provides a new tool for studying the associations between the SLA region and zootechnical traits.


Vital Signs Directed Therapy for the Critically Ill: Improved Adherence to the Treatment Protocol Two Years after Implementation in an Intensive Care Unit in Tanzania.
Treating deranged vital signs is a mainstay of critical care throughout the world. In an ICU in a university hospital in Tanzania, the implementation of the Vital Signs Directed Therapy Protocol in 2014 led to an increase in acute treatments for deranged vital signs. The mortality rate for hypotensive patients decreased from 92% to 69%. In this study, the aim was to investigate the sustainability of the implementation two years later. An observational, patient-record-based study was conducted in the ICU in August 2016. Data on deranged vital signs and acute treatments were extracted from the patients' charts. Adherence to the protocol, defined as an acute treatment in the same or subsequent hour following a deranged vital sign, was calculated and compared with before and immediately after implementation. Two-hundred and eighty-nine deranged vital signs were included. Adherence was 29.8% two years after implementation, compared with 16.6% (p < 0.001) immediately after implementation and 2.9% (p < 0.001) before implementation. Consequently, the implementation of the Vital Signs Directed Therapy Protocol appears to have led to a sustainable increase in the treatment of deranged vital signs. The protocol may have potential to improve patient safety in other settings where critically ill patients are managed.


Heparin 'flush' induced thrombocytopenia triggered by total hip replacement: a case report.
Heparin-induced thrombocytopenia (HIT) typically responds to heparin termination. Some types of HIT can persist after heparin discontinuation. A 95-year-old woman was referred to the cardiology from orthopaedics because of acute limb ischaemia (ALI) 1 day after surgery of a femoral neck fracture. Despite thrombectomy, ALI relapsed the next day. She had been treated with intravenous antibiotics with a diagnosis of aspiration pneumonia for 1 week until 3 days before surgery, together with heparin flush twice a day. Of note, no intra-/post-operative heparin was administered, no cell salvage device, central venous, nor arterial catheters were used before development of ALI. The patient and her family refused reattempting invasive therapies; consequently, the patient continued to worsen and died on post-operative day 3. Diagnosis of autoimmune HIT, which was prompted by surgery without re-exposure to heparin, was confirmed posthumously. This case emphasizes the significance of suspecting autoimmune HIT in any patient presenting with thrombosis, even if the heparin exposure dates back more than a few days or even without heparin exposure.


Everyday Discrimination among African American Men: The Impact of Criminal Justice Contact.
The present study examined the impact of criminal justice contact on experiences of everyday discrimination among a national sample of African American men. African American men have a high likelihood of being targets of major discrimination, as well as experiencing disproportionate contact with the criminal justice system. Few studies, however, examine everyday discrimination (e.g., commonplace social encounters of unfair treatment) among this group. Using data from the National Survey of American Life, we provide a descriptive assessment of different types of everyday discrimination among African American men. Specifically, we examined differences in everyday discrimination among men who have never been arrested, those who have been arrested but not incarcerated, and men who have a previous history of criminal justice intervention categorized by type of incarceration experienced (i.e., reform school, detention, jail, or prison). Study findings indicated overall high levels of reported everyday discrimination, with increased likelihood and a greater number of experiences associated with more serious forms of criminal justice contact. However, in many instances, there were no or few differences in reported everyday discrimination for African American men with and without criminal justice contact, indicating comparable levels of exposure to experiences with unfair treatment.


[Arterial oxygen saturation during ascent of a mountain higher than 8,000 meters].
Arterial oxygen saturation (SaO2) diminishes with altitude. To know the values of SaO2 in healthy mountaineers during the ascent of a mountain higher than 8,000 metres. On occasion of an expedition to Gasher brum II (8,035 m), SaO2 at rest was measured by pulse oxymetry during the approach march, in the base camp (on day one and one month later), in camps II and III, during the assault at 7,500 m and on the summit. During the approach march, the SaO2 in Paiju (3,365 m) was 92.9 +/- 1.4% and in Gore II (4,250 m) 85.0 +/- 4.3%. In the base camp (5,200 m) it was 78.4 +/- 9.5% on the first day and 87.4 +/- 3.0% one month later (p < 0.007). In camp II (6,500 m) it was 72.7 +/- 6.7%. In camp III (7,000 m) it was 68.0 +/- 9.3% (recorded on 21 asymptomatic climbers). At this altitude a SaO2 of 40% was recorded during sleep in an asymptomatic subject, apparently without apnoeic crises. During the assault at 7,500 m, SaO2 was 60.5 +/- 13.5% (measured on 4 climbers). On the summit (8,035 m) the SaO2 of two subjects was 84% and 88%, respectively. During expeditions to mountains higher than 8,000 metres, mountaineers have extremely low values of SaO2, similar to those of patients with severe respiratory failure. SaO2 increases progressively with acclimatization. SaO2 on the summit could have been relatively high, probably because of hyperventilation.


RB regulation of developmental transcriptional programs.
Inactivation of the retinoblastoma protein (pRB) is a hallmark of human cancer. Accordingly the RB pathway has been extensively studied in mammals, flies and worms, but mostly in the context of cell cycle entry. The means by which RB proteins regulate differentiation and the transcription of genes involved in differentiation and development is less well understood. We have examined how Drosophila RB proteins regulate differentiation-specific genes in proliferating cells. We found that the mechanism of repression differs from what has been observed at cell cycle regulated genes (Figure 1). Two different chromatin modifications present at different locations contribute to the repression of such genes. We argue that this represents a novel mechanism of repression and that this type of regulation by RB proteins warrants further attention.


Implementation of sexual and gender minority health curricula in health care professional schools: a qualitative study.
Lesbian, gay, bisexual, transgender, queer, and intersex people-inclusively termed "sexual and gender minorities"-have unique health and health care needs that are not being met by most healthcare providers due to lack of training in health care professional schools. The purpose of this qualitative study was to examine implementation factors for advancing sexual and gender minority health professional student curricula in academic settings. Semi-structured interviews guided by the Consolidated Framework for Implementation Research (CFIR) were conducted with sixteen curricular champions to identify factors relevant to curricular adoption, integration, and sustainment. Themes were coded using a hybrid of deductive and inductive approaches and reported using major CFIR domains. Facilitators supporting implementation of sexual and gender minority health curricula included collaboration among multiple stakeholders, alignment of formal and hidden curricula, fostering an organizational culture that valued inclusion and diversity, engagement with external subject matter experts or faculty with content expertise, and thoughtful and inclusive planning. This study contributes to health care professional education research as well as to implementation science. Facilitators that were identified in this study can be used to increase the adoption, integration, and sustainment of sexual and gender minority health curricula in diverse academic settings.


Response Changes During Insertion of a Cochlear Implant Using Extracochlear Electrocochleography.
Electrocochleography is increasingly being utilized as an intraoperative monitor of cochlear function during cochlear implantation (CI). Intracochlear recordings from the advancing electrode can be obtained through the device by on-board capabilities. However, such recordings may not be ideal as a monitor because the recording electrode moves in relation to the neural and hair cell generators producing the responses. The purposes of this study were to compare two extracochlear recording locations in terms of signal strength and feasibility as intraoperative monitoring sites and to characterize changes in cochlear physiology during CI insertion. In 83 human subjects, responses to 90 dB nHL tone bursts were recorded both at the round window (RW) and then at an extracochlear position-either adjacent to the stapes or on the promontory just superior to the RW. Recording from the fixed, extracochlear position continued during insertion of the CI in 63 cases. Before CI insertion, responses to low-frequency tones at the RW were roughly 6 dB larger than when recording at either extracochlear site, but the two extracochlear sites did not differ from one another. During CI insertion, response losses from the promontory or adjacent to the stapes stayed within 5 dB in ≈61% (38/63) of cases, presumably indicating atraumatic insertions. Among responses which dropped more than 5 dB at any time during CI insertion, 12 subjects showed no response recovery, while in 13, the drop was followed by partial or complete response recovery by the end of CI insertion. In cases with recovery, the drop in response occurred relatively early (<15 mm insertion) compared to those where there was no recovery. Changes in response phase during the insertion occurred in some cases; these may indicate a change in the distributions of generators contributing to the response. Monitoring the electrocochleography during CI insertion from an extracochlear site reveals insertions that are potentially atraumatic, show interaction with cochlear structures followed by response recovery, or show interactions such that response losses persist to the end of recording.